Introduction: Treatment of osteoporosis with high-dose fluoride alone does not reduce fracture risk. We hypothesized that the anti-fracture efficacy of fluoride could be optimized by its use in low doses combined with an antiresorptive agent.

Experimental Subjects: 80 women with postmenopausal osteoporosis who had been taking estrogen for 1 year.

Methods: Subjects were randomized to receive monofluorophosphate (fluoride content of 20 mg/day) or placebo over 4 years in a double-blind trial.

Results and Discussion: There were progressive increases in lumbar spine bone density (BMD) over the duration of the study (MFP 22%, placebo 6%, P<0.0001). In the trabecular bone of L3, these increases were even greater (MFP 49%, placebo 2.5%, P<0.0001). In the proximal femur there were smaller but significant treatment effects (P=0.015). Total body scans and their subregions also showed significantly greater increases in the MFP group. Bone formation markers increased significantly in the MFP group at year 1. Hyperosteoidosis was present in biopsies from 5 of 7 MFP subjects, with osteomalacia in 2 of 7. The hazards ratio for vertebral fractures was 0.20 (95% confidence interval 0.05-1.30) and the incidence rate ratio was 0.12 (95% confidence interval, 0.06-0.23, P<0.01). The hazards ratio for non-vertebral fractures was 3.3 (95% CI 0.8-12.0).

We conclude that fluoride 20 mg/day produces substantial increases in BMD, but still interferes with bone mineralization. This indicates that most previous studies with this ion have used toxic doses, and that much lower doses should be assessed to find a safe dose window for the use of this powerful anabolic agent.